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IL-27 Regulates IL-10 and IL-17 from CD4⁺ Cells in Nonhealing Leishmania major Infection¹

Charles F. Anderson^*, Jason S. Stumhofer, Christopher A. Hunter and David Sacks^2,*

^* Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104

Control of infection caused by Leishmania major requires the development of IFN-⁺CD4⁺ lymphocytes for the induction of microbicidal activity in host macrophages. We recently reported on the inability of conventionally resistant C57BL/6 mice to successfully resolve infection by an isolate of L. major, despite a strong IFN- response by the host. Susceptibility was caused by Ag-specific IL-10 from CD4⁺ cells that were also producing IFN-. In the present studies, we have explored the role for IL-27 in the regulation of IL-10 from Th1 cells in leishmaniasis. Cytokine analysis of CD4⁺ cells in the lesions and draining lymph nodes of infected IL-27R-deficient (WSX-1^–/–) mice revealed diminished IL-10 from IFN-⁺ CD4⁺ cells, which was accompanied by a reduction in total IFN-⁺CD4⁺ cells and an increase in IL-4. Despite the inhibition of IL-10 from CD4⁺ cells, no significant change in parasite numbers was observed, due both to the shift in the Th1/Th2 balance and to residual levels of IL-10. Strikingly, infected WSX-1^–/– mice developed more severe lesions that were associated with the appearance of IL-17⁺ CD4⁺ cells, demonstrating a function for IL-27 in blocking the development of inappropriate Th17 cells during L. major infection. The results demonstrate the pleiotropic effects that IL-27 has on L. major-driven Th1, Th2, and Th17 development, and reinforce its function as a key regulatory cytokine that controls the balance between immunity and pathology.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and in part by National Institutes of Health Grants AI 142334 and D43 TW007127.

² Address correspondence and reprint requests to Dr. David Sacks, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4, Room 126, 4 Center Drive, MSC 0425, Bethesda, MD 20892-0425. E-mail address: dsacks{at}niaid.nih.gov

³ Abbreviation used in this paper: dLN, draining lymph node.